A variety of gene products have been implicated in the pathogenesis of dementias of the Alzheimer type (DAT), the most common forms of dementias in the elderly. A key unsolved problem has been how these several proteins may interact to cause the two major types of pathology, deposits of beta amyloid (Ab) and the collections of abnormal forms of tau protein, the main constituent of neurofibrillary tangles (NFT). The present proposal addresses the potential role of an adaptor protein called FE65 in such interactions. FE65p (FE65 protein) binds to an intracellular domain of the precursor protein (bPP) of Ab and to several other proteins. When overexpressed, it increases the rate of bPP trafficking and Ab production. Our new evidence [using FE65 (FE65 gene) knockout mice] also supports a role for FE65 in the regulation of the expression of a kinase implicated in the altered phosphorylation of tau protein (glycogen synthase kinase-3b or tau protein kinase I) (GSK-3b). We have also found cytochemical evidence for the co-localization of FE65p with tau in DAT brains. Using our FE65 knockout mice, we now propose to investigate the mechanisms whereby FE65 regulates expression of GSK-3b and several other candidate genes. We suggest that this regulation is via CP2/LBP-1/LSF (CP2) transcription elements, since FE65p directly binds to CP2. We will also investigate the role of FE65 on Ab production/deposition and the rate of bPP internalization, using FE65 knockout mice and knockout mice crossed with the Tg2576 line, which overexpress a familial DAT mutant bPP.